This program consists of collaborative projects on molecular aspects of the normal and pathological brain aging, focused on neuronal fibrous protein structures: neurofilaments and microtubules. Particular attention will be given to molecular abnormalities seen in Alzheimer disease post mortem brain tissue. Extensive analyses will be carried out on the hallmark neuronal lesion of this disease entity, the paired helical filament. Four interrelated projects are proposed: (1) The molecular structure and subcellular distribution of human, mouse and rabbit neurofilament and microtubule proteins; studies on normal age-related alterations in mammalian CNS fibrous proteins; the normal aging of the synaptic architecture. (II) Macromolecular changes in human and animal brain aging at the level of messsenger RNA, protein synthesis and post-translational modification. (III) Alterations of neurofilament subunits and mRNA translation products in an experimental (aluminum) model of fialmentous degeneration of neurons. (IV) Macromolecular alterations affecting neurofilament subunits in human neuronal aging and in dementia of the Alzheimer type. This Program will be carried out as a collaborative effort by Neurochemistry and Neuropathology Laboratories of the Mailman Research Center, McLean Hospital, a division of the Massachusetts General Hospital and affiliated with the Harvard Medical School.